Prolactin receptor-mediated activation of pSTAT5 in the pregnant mouse brain.

Pregnancy represents a period of remarkable adaptive physiology throughout the body, with many of these important adaptations mediated by changes in gene transcription in the brain. A marked activation of the transcription factor signal transducer and activator of transcription 5 (STAT5) has been described in the brain during pregnancy and likely drives some of these changes. We aimed to investigate the physiological mechanism causing this increase in phosphorylated STAT5 (pSTAT5) during pregnancy. In various tissues, STAT5 is known to be activated by a number of different cytokines, including erythropoietin, growth hormone and prolactin. Because the lactogenic hormones that act through the prolactin receptor (PRLR), prolactin and its closely-related placental analogue placental lactogen, are significantly increased during pregnancy, we hypothesised that this receptor was primarily responsible for the pregnancy-induced increase in pSTAT5 in the brain. By examining temporal changes in plasma prolactin levels and the pattern of pSTAT5 immunoreactivity in the hypothalamus during early pregnancy, we found that the level of pSTAT5 was sensitive to circulating levels of endogenous prolactin. Using a transgenic model to conditionally delete PRLRs from forebrain neurones (Prlrlox/lox /CamK-Cre), we assessed the relative contribution of the PRLR to the up-regulation of pSTAT5 in the brain of pregnant mice. In the absence of PRLRs on most forebrain neurones, a significant reduction in pSTAT5 was observed throughout the hypothalamus and amygdala in late pregnancy, confirming that PRLR is key in mediating this response. The exception to this was the hypothalamic paraventricular nucleus, where only 17% of pSTAT5 immunoreactivity during pregnancy was in PRLR-expressing cells. Taken together, these data indicate that, although there are region-specific mechanisms involved, lactogenic activity through the PRLR is the primary signal activating STAT5 in the brain during pregnancy.